Maturation alters the pulmonary arterial response to hypoxia and inhaled nitric oxide in the presence of endothelial dysfunction.

Surgical intervention in ever younger patients has led to a new appreciation of the unique physiology of the neonate. Specifically, newborn patients may respond very differently to hypoxic episodes and subsequent treatment with inhaled nitric oxide than older infants. In the current study, we examined differences in the pulmonary arterial response to hypoxia and inhaled nitric oxide in 48-hour-old (n = 8) and 14-day-old (n = 8) Yorkshire pigs in a model of nitric oxide synthase inhibition, as might be seen with endothelial dysfunction. Data were acquired after treatment with the nitric oxide synthase inhibitor N omega-nitro-L-arginine during hypoxia (inspired oxygen fraction = 0.10) and during inhalation of nitric oxide (100 ppm). Input mean impedance, reflecting distal arteriolar vasoconstriction, and characteristic impedance, reflecting proximal arterial geometry and distensibility, were calculated. The modulus of elasticity, a measure of the "stiffness" of the proximal vessels, was also calculated. Hypoxia caused a large increase in input mean impedance in both 48-hour-old and 14-day-old pigs (4826 +/- 272 versus 8744 +/- 488 dyne.cm.sec-5 and 3129 +/- 73 versus 6000 +/- 134 dyne.cm.sec-5, respectively; p = 0.0078). Characteristic impedance was not altered in the younger animals (1171 +/- 76 dyne.cm.sec-5) but increased in the older animals (419 +/- 15 versus 797 +/- 20 dyne.cm.sec-5. p = 0.0078). Older animals also experienced an increase in the modulus elasticity (1.92E06 +/- 3.2E05 versus 1.05E07 +/- 3.9E05 dyne/cm2, p = 0.0078). These data show that inhibited nitric oxide production, as might be seen in endothelial dysfunction, potentiates the profound hypoxic vasoconstriction observed at the level of the distal pulmonary arterioles in both neonatal and infant animals. In contrast, only older animals had a stiffening of the larger, more proximal vessels with hypoxia. In both age groups, inhaled nitric oxide effectively reduced the increases in impedance.

Pulmonary arterial endothelial dysfunction potentiates hypercapnic vasoconstriction and alters the response to inhaled nitric oxide.

BACKGROUND: Pulmonary hypertensive crisis can be initiated by episodes of hypercapnic acidosis. Hypercapnic vasoconstriction in the newborn pulmonary arterial circulation may be modulated by endogenous production of nitric oxide (NO) by the endothelial cell and effectively treated with inhalation of NO. METHODS: Sixteen 48-hour-old piglets were randomized to receive a hypercapnic challenge after administration of either saline vehicle or the NO synthase inhibitor N-omega-nitro-L-arginine (L-NA). Pulmonary arterial pressure, flow, and radius measurements were taken at baseline, after infusion of vehicle or L-NA, during hypercapnia (inspired fraction of carbon dioxide, 0.15), and during inhalation of NO (100 ppm). Fourier analysis was used to calculate input mean impedance, reflecting distal arteriolar vasoconstriction, and characteristic impedance, reflecting proximal arterial geometry and distensibility. RESULTS: Input mean impedance was increased with L-NA administration. Animals pretreated with L-NA also underwent a much larger increase in input mean impedance with exposure to hypercapnia than untreated animals. Characteristic impedance increased in the treated animals, but not in the controls. CONCLUSIONS: In the newborn pulmonary arterial circulation, endogenous NO production by the endothelial cell modulates resting tone distally, but not proximally. In addition, lack of a functional endothelium markedly potentiates the distal vasoconstrictor response to hypercapnia and produces proximal vasoconstriction. Despite impaired endothelial function, inhaled NO remains an effective vasodilator in hypercapnic pulmonary vasoconstriction.